Tricholine citrate (hereinafter "TCC") is an ester of citric acid with three choline molecules.
Citric acid is a hydroxy tricarboxylic acid. Since the discovery by van Scott et al., "Control of Keratinization with .alpha.-Hydroxy Acids and Related Compounds", Arch. Dermatol., Vol. 110, October 1974, pp. 586-590, that hydroxyacids are effective for the treatment of hyperkeratotic disorders of the skin, several hydroxy acids and related compounds have been used extensively in dermatologic and cosmetic preparations. The reported cosmetic properties of hydroxy acids include improved skin texture, improved skin brightness and firmness, decreased wrinkling and decreased pigmentation. See e.g., Berardesca et al., "AHA Mechanisms of Action", Cosmetics & Toiletries, Vol. 110, June 1995, pp. 30-31.
Triesters of citric acid with alkyl or aryl groups have been claimed to have anti-aging and UV protecting effects. See e.g., Natraj et al., U.S. Pat. No. 5,244,665. Triethyl and tributyl esters of citric acid have been shown to be effective in the treatment of photodamaged and/or hyperpigmented skin, and in slowing down the aging process, in addition to the photoprotective action. The use of TCC, however, has not been taught or suggested for use in skin treatment compositions. Natraj et al. do not appear to teach or suggest either TCC or any nitrogen or amine-containing citrate esters.
Choline is an essential nutrient for phospholipid, sphingolipid and sphingomyelin biosynthesis in all cells. In addition, choline acts as a methyl donor for carnitine biosynthesis which is required for normal fatty acid turnover. Choline deficiency results in reduced lipoprotein biosynthesis, decreased membrane turnover and increased triglyceride accumulation. Choline deficiency in the epidermis could result in lower barrier lipid formation leading to an abnormal water barrier and poor skin condition. Choline in the form of phosphatidyl choline or phosphoryl choline and their derivatives have been used in cosmetic compositions and have been claimed to have multiple beneficial effects on skin, such as anti-fungal effects, wound healing enhancers, dry skin benefits, improving transepidermal water loss, moisturizing effects, anti-acne effects, UV protecting effects, conditioning benefits, humectant effects, and anti-inflammatory effects. See U.S. Pat. No. 5,391,550; U.S. Pat. No. 5,376,646; Abstract of German Patent Application No. 4 310 015; Abstract of Japanese Patent Specification No. 6179613; Abstract of Soviet Union Patent Specification No. 1811403; Abstract of European Patent Application No. 0 479 121; U.S. Pat. No. 5,166,139. Patented compounds include phosphatidyl choline, phosphoryl choline, acylated choline, sphingomyelin or their derivatives.
Choline salicylate has been employed as an anti-inflammatory and analgesic agent for topical use. See U.S. Pat. No.4,275,059 (Flora et al.).
TCC is a common inexpensive chemical used in the past as an effective iron chelator. See Rosenfelder, U.S. Pat. No. 2,865,938. TCC has been used to stabilize animal growth hormone preparations (see Hamilton et al., U.S. Pat. No. 4,816,568) and to treat iron deficiency anemia (see Feigh et al., U.S. Pat. No. 3,395,229). No toxicity or adverse effects have been associated with this molecule since its individual components, citric acid and choline, are naturally occurring metabolites in cells.
Skin treatment or cosmetic compositions containing tricholine citrate have not been disclosed. None of the art described above teaches the use of TCC for the growth of skin cells or skin cell cultures. Furthermore, the art does not appear to teach or suggest the use in cosmetic compositions of any citrate ester wherein citric acid is esterified with any compound which serves as an essential nutrient for skin cells.
The top layer of human skin or the epidermis is composed of many different cell types including keratinocytes, melanocytes and langerhans cells. Keratinocytes are the major cell type of the epidermis (75-80% of the total number of cells in the human epidermis). Within the epidermis the keratinocytes reside in four distinct stages of differentiation. The basal layer rests on the basal lamina separating epidermis from the dermis. These cells are large columnar rapidly proliferating cells. These basal cells migrate upward within the epidermis, initiated by the process of differentiation. The layer above the basal cells is the spinous layer. The cells in the spinous layer initiate the production of proteins characteristic of the differentiated epidermis. The granular layer, lying above the spinous layer, is characterized by electron-dense granules. This layer is responsible for the synthesis of lipid molecules required for the formation of the water impermeable barrier of the skin. The topmost layer of the skin, the stratum corneum, is formed from the granular layer by the destruction of cellular organelles. The cells in the stratum corneum, corneocytes, contain extensively cross-linked proteins, surrounded by a highly resistant cell envelope. The corneocytes are embedded in a bed of specific lipid structures (analogous to bricks on a bed of mortar) and this structure provides the protective barrier for the skin. The outermost layer of corneocytes is peeled off from the skin during the normal process of desquamation. Differentiation of the epidermal keratinocytes is the driving force for the normal desquamation process to occur. Epidermal differentiation is important for providing the essential function of the skin, namely to provide a protective barrier against the outside environment and to prevent loss of water from the body. The rate of synthesis of DNA, determined by the incorporation of radiolabeled substrate [.sup.3 H]thymidine, is an indicator of keratinocyte proliferation. An increase in cornified envelopes and the enzyme transglutaminase, which is responsible for the formation of cornified envelopes, indicates an increase in keratinocyte differentiation. The basal cells which have the highest rate of growth, are the least differentiated. The most differentiated cells of the stratum corneum do not have the ability to proliferate. The increased proliferation of the basal cells is the driving force for the differentiation of the upper layer cells to form corneocytes.
The present invention is based, in part, on the discovery that TCC induces cell proliferation and increases cellular lipid levels in skin, both of which in turn result in increased benefits to skin, such as improved conditioning, improved youthful appearance, decrease in wrinkle appearance, moisturizing, and improvement in the appearance of photodamaged skin.
Accordingly, it is an object of the present invention to provide compositions for the treatment of skin using TCC as the active ingredient.
It is another object of the invention to provide a method for treating the appearance of wrinkled, flaky, aged, or photodamaged skin and for promoting youtful appearance.
These and other objects of the invention will become more apparent from the detailed description and examples which follow.